Role of the TGF- b /Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension

Rationale : Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF- b receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF- b family signalinginPHandpulmonaryvascularremodelingremainsunclear. Objectives : To determine whether inhibition of TGF- b signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH). Methods : We have used an orally active small-molecule TGF- b receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH. Measurements and Main Results : The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF- b signalingasdocumentedbypsmad2expression.Inhibitionof TGF- b signaling with SD-208 significantly attenuated the develop- ment of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF- b signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions : These findings provide evidence that increased TGF- b signaling participates in the pathogenesis of experimental severe PH.

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